Thienodiazepine compounds

ABSTRACT

WHEREIN X is a member selected from the group consisting of a hydrogen atom, a halogen atom, a trifluoromethyl group, an alkoxy group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms; each of R1 and R2 is a member selected from the group consisting of a hydrogen atom and an alkyl group having 1 to 4 carbon atoms, or R1 and R2 together form a tetramethylene group, i.e. -(CH2)4-; and R is a member selected from the group consisting of -CH CH-, -N N- and -CO-O-; and pharmaceutically acceptable acid addition salts thereof are disclosed. They are useful as minor tranquilizers.   Thienodiazepine compounds of the formula:

United States Patent I1 1 Nakanishi et al.

[ Nov. 18, 1975 1 THIENODIAZEPINE COMPOUNDS [75] Inventors: Michio Nakanishi, Nakatsu; Tetsuya Tahara, Fukuoka; Kazuhiko Araki, Fukuoka; Masami Shiroki, Fukuoka, all of Japan [73] Assignee: Yoshitomi Pharmaceutical Industries, Ltd., Osaka, Japan [22] Filed: June 21, 1973 [21] Appl. No.: 372,354

[30] Foreign Application Priority Data June 22, 1972 Japan 47-63028 July 3, 1972 Japan 47-66923 July 3, 1972 Japan 47-66924 [52] US. Cl.... 260/309; 260/239.3 T; 260/239.3 B; 260/307 A; 260/308 D; 260/329 F; 260/332.3 P; 260/332.5; 424/269; 424/272;

Robba et al., Chem. Abstracts, Vol. 69, Abstract No. 96635j (1968).

Robba et al., Chem. Abstracts, Vol. 69, Abstract No. 27365j (1968). Hester et al., Chem. Abstracts, Vol. 78, Abstract No. 136353K (1973).

Primary Examiner-Alton D. Rollins Attorney, Agent, or FirmSughrue, Rothwell, Mion, Zinn & Macpeak [57] ABSTRACT Thienodiazepine compounds of the formula:

wherein X is a member selected from the group consisting of a hydrogen atom, a halogen atom, a trifluoromethyl group, an alkoxy group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms; each of R and R is a member selected from the group consisting of a hydrogen atom and an alkyl group having 1 to 4 carbon atoms, or R and R to- I gether form a tetramethylene group, i.e. (Cl-l and R is a member selected from the group consisting of CH=CH, -N=N- and COO; and pharmaceutically acceptable acid-addition salts thereof are disclosed. They are useful as 'minor tranquilizers.

3 Claims, No Drawings The Compounds of formula [I] can be produced by the following methods (i) to (iii). i. In the case of compounds of formula [I] wherein R is CH=Cl-l; by subjecting a compound of the formula:

THIENODIAZEPINE COMPOUNDS This invention relates to novel and therapeutically valuable thieno[2,3-e][1,4]diazepine compounds of 5 the formula: v Q

and pharmaceutically acceptable acid addition salts thereof, wherein X is a member selected from the h i X, R d R are as defi d ab and Y i 0 group consisting of a hydrogen atom, a halogen atom r (0R [wherein R is an alkyl group having 1 to 4 g- F, C1 3 trifluoromethyl group, an alkoxy carbon atoms (e.g. methyl, ethyl, propyl or butyl) or an group having 1 to 4 carbon atoms -gmethoxy, aralkyl group (e.g. benzyl)], to intramolecular condenoxy, propoxy or butoxy) and an alkyl group having 1 to Satiom 4 carbon atoms -gmethyl, ethyl, p py or y The reaction is usually carried out in an inert solvent each of and R2 is a member Selected from the group (e.g. methanol, ethanol, dioxane, dimethylformamide, Consisting of a y g atom and ah alkyl group tetrahydrofuran or benzene, or a mixture thereof) at a ihg 1 to 4 carbon atoms methyl, ethyl, p p temperature of from room temperature to about 150C y or and R2 together form a tetramethylene for a period of from an hour to several hours, advanta- S P -z)4 and R is a member Selected geously in the presence of an acid catalyst (e.g. hydrofrom the g p consisting of N=N chloric acid, sulfuric acid, polyphosphoric acid, formic and acid, acetic acid, propionic acid, methanesulfonic acid I Compounds of the formula: or p-toluenesulfonic acid) under reflux. The reaction can also be carried out without a solvent. In such a Ar case, the starting compound of formula [II] is preferably fused at a temperature somewhat higher than its H melting point, usually at a temperature between about 2 5 N c 2 150C and about 220C. R Tautomerism is encountered in the compounds of formula [II]:

wherein X, R, R and Y are as definedabove. In this specification, however, these compounds are named as wherein Ar is a member selected from the group consisting of an optionally substituted phenyl group and a pyridyl group; each of R and R is a member selected the compounds of formula [II].

from the group consisting of a hydrogen ato and an The starting compounds of formula [II] wherein Y is alkyl group having 1 to 4 carbon atoms, or R and R (0R can be produced by reacting a compound of the together form a tetramethylene group i.e. (CH for l and R is a member selected from the group consisting I of a hydrogen atom, an alkyl group having 1 to 4 carbon atoms and an optionally substituted phenyl group, are disclosed in US. Pat. Application Ser. No. 261757 as having utility as minor tranquilizers. They have a fairly strong ataxia-inducing action which may cause adverse effects such as lassitude, dizziness and disturbance in walking. Conventional minor tranquilizers, for example diazepam, mostly show a considerably strong ataxia-inducing action, too. On the contrary, the com- /C is g C CH pounds of present invention are far less potent in the said action than the prior art compounds.

wherein X, R and R are as defined above, with an aminoacetal of the formula:

R nmcmcu [v1 Q x OR l . [v1 I I R wherein R is as defined above, in an inert solvent, ad- 5 I s I vantageously under heating. N

The compound of formula [II] wherein Y is 0 can be H obtained by hydrolysis of the compound of formula [II] wherein Y is (OR ii. In the case of compounds of f l [I] wherein R is by reacting a wherein X, R and R are as defined above, with phospound of formula: gene- The reaction is usually carried out in an inert solvent (e.g. benzene, toluene, xylene, chloroform, methylene Q chloride, diethyl ether, tetrahydrofuran or dioxane) at 1 a temperature of from room temperature to a refluxing R C Q [VI] temperature, if necessary, in the presence of a deacidi- Z H S [I Z fying agent such as triethylamine or pyridine.

N: Tautomerism is once more encountered in the com- N pounds of formula [VIII]:

i I X E li 'X R1 [C i R ==N\ CH CH 2 E 2 21 L 2 H NHOH whereinX, R and R are as defined above, with nitrous wherein, X, R and R are as defined above. In this acid. specification, however, these compounds are named as More particularly, the compound of formula [VI] is 2-hydroxyimino compounds of formula [VIII]. allowed to react with an aqueous solution of an alkali The starting compounds of formula [VIII] can be metal salt of nitrous acid (e.g. sodium nitrite or potasprepared, for example, by reacting the compound of sium nitrite). formula [IV] with hydroxylamine.

The reaction is usually carried out in an aqueous so- The compounds of formula [I] can be converted into lution below 50C for a period of from a few minutes to 40 the corresponding acid addition salts in a conventional several hours. The reaction is forced to completion by manner by treating. the compounds with various inortreatment of a suitable alkali (e.g. sodium carbonate, ganic and organic acids, for example, hydrochloric, sulpotassium carbonate, sodium hydroxide or potassium furiC, hydrobromic, Ph Ph iC, nitric, methanesulhydroxide). fonic, p-toluenesulfonic, acetic, oxalic, maleic, fu-

Tautomerism is encountered again in the compounds maric, citric and camphorsulfonic acids. of form l [VI]; The compounds of formula [I] and pharmaceutically 2 31 2 l cu R S =c R S I 2 I N C\\ Hz H NNH2 [VI] [VII 1 wherein X, R and R are as defined above. In this specacceptable acid addition salts thereof are strong in supification, however, these compounds are named as 2- pression of fighting behavior and anticonvulsant effect, hydrazine compounds of formula [VI]. but very weak in ataxia-inducing action as shown, for

The starting compounds of formula [VI] can be pre-' example, by the following tests. pared, for example, by the method disclosed in Pub- I. Suppression of Fighting Behavior lished West German Pat. Application OLS-2229845, Fighting episodes were produced in mice by the namely by reacting the compound offormula [IV] with method described by Tedeschi et al. in the Journal of hydrazine. iii. In the case of compounds of formula [I] Pharmacology and Experimental Therapeutics, vol.

wherein R is COO; by reacting a compound of 125, p. 28 ff. (1959). Groups of8 female mice (4 pairs) 1 the formula: were given the test compound orally 60 minutes prior to receiving an electric foot-shock for 3 minutes with a 530 volt interrupted direct current, 1.3 milliampereas, cycles per second. The exhibition of 3 fighting episodes or less within the 3 minute electric foot shock treatment was deemed to be a suppression of the fighting behavior by the test compound. 81 pairs of control mice had shown an 8.7 fighting episode average under the same conditions without administration of the test compound. The ED the dose required to suppress 50% of fighting pairs was determined graphically.

II. Anticonvulsant Effect Pentylenetetrazole (150 mg/kg) was administered subcutaneously to groups consisting of 6 mice minutes after the intraperitoneal administration of the test compound. The number of dead mice was counted 3 hours after the administration of pentylenetetrazole, and then the ED the dose required to suppress the motality rate to 50%, was determined graphically.

Ill. Ataxia-Inducing Action (Rotating-Cage Method) Groups of 10 female mice each were placed on the horizontal metal wire mesh cage cm diameter, 8 mm wire mesh) rotating at a speed of 13 rpm. The number of mice which had dropped from the cage within 1 minute was determined. The tests were performed 1 hour after the intraperitoneal administration of the test compounds. The ED the dose required to cause 50% of the animals to fall off the cage, was determined graphically.

Compounds A and DZP are identified below:

A: 6-o-chlorophenyl-8-ethyl-4I-I-imidazo[2, 1 c]thieno[2,3-e][1,4]diazepine DZP: Diazepam In view of the tests above, the compounds of formula [I] and pharmaceutically acceptable acid addition salts thereof are more potent in suppression of fighting behavior and anticonvulsant effect, and less potent in ataxia-inducing action than Diazepam which is representative one of conventional minor tranquilizers. Seeing this in clinical respect, it can be said that the compounds of formula [I] and pharmaceutically acceptable acid addition salts thereof have less side effects such as lassitude, dizziness or disturbance in walking than the conventional tranquilizers, which side effects are caused by the said ataxia-inducing action.

In view of various tests, including those mentioned above, the compounds of the invention represented by formula [I] and pharmaceutically acceptable acid addition salts thereof can be safely administered orally as minor tranquilizers (antianxiety drugs) for the treatment of neurosis, anxiety, tension and depressive states, in the form of a pharmaceutical preparation with a suitable and conventional pharmaceutically acceptablecarrier or adjuvant, without adversely affecting the patients.

The pharmaceutical preparations can take any conventional form such as tablets, capsules or powders.

Formulation Examples (a) Tablets each containing 1 mg of an active ingredi- 7 (b) An 1% powder is prepared compositions: Compound [I] Lactose Methyl Cellulose 1 Silicon Dioxide l from the following 1% by weight 97 The daily dose of compound [I] or a salt thereof for human adults usually ranges from about 2 to 24 mg. in single or multiple dose, but it may vary depending upon the age, body weight, and/or severity of the conditions to be treated as well as the response to the medication.

The present invention will be better understood from the following examples, but they are not to be construed as limiting the present invention.

EXAMPLE 1 A solution of 7.0 g of 5-o-chlorophenyl-2-(2,2-diethoxyethylamino)-3I-I-thieno[2,3-e][1,4]diazepine in 60 ml of glacial acetic acid is refluxed moderately for 2 hours. After cooling, the acetic acid is distilled off under reduced pressure. The residue obtained is alkalified with an aqueous sodium carbonate solution, and the solution is extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and concentrated under reduced pressure. To the viscous oil obtained is added a mixture of ligroin and ethyl acetate (9:1 and the precipitated crystals are collected by suction filtration. The crystals (5.1g) are recrystallized from a mixture of ligroin and ethyl acetate (9:1) to give 6-o-chlorophenyl-8-ethyl-4H-imidazo[2,1- c]thieno[2,3-e][1,4]-diazepine as colorless plates melting at 124127C. This product is treated with alcoholic hydrochloric acid, and the corresponding hydrochloride as colorless crystalline powder shows a melting point of 243245C (from acetone).

EXAMPLE 2 2.5 g of 2-(2,2-diethoxyethylamino)-7-ethyl-5-phenyl-3l-l-thieno[2,3-e][1,4]diazepine is heated at C on an oil bath for 15 minutes. After cooling, the resultant is dissolved in ethyl acetate. The solution is filtered with activated charcoal, and the filtrate is concentrated. Ligroin is added to the residue, and the precipitated crystals are collected by suction filtration. The

crystals are recrystallized from ligroin to give 1.5 g of 8-ethyl-6-phenyl-4l-l-imidazo[2,1-c]-thieno[2,3- e][1,4]diazepine as colorless needles melting at 96-98C.

EXAMPLE 3 To a mixture of 4.2 g of 2-(2,2-diethoxyethylamino)- 5-phenyl-6,7,8,9-tetrahydro-3I-l-[ l ]benzothieno[2,3' e][ 1,4]diazepine and 50 ml of ethanol is added 5 drops of concentrated sulfuric acid, and the mixture is refluxed for 2 hours. The solvent is distilled off under reduced pressure. The residue is alkalified with a 10% sodium carbonate solution, and the solution is extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and concentrated uner reduced pressure. The crystalline residue obtained is recrystallized from a mixture of ligroin and ethyl acetate (1:1) to give 2.5 g of 6-phenyl-7,8,9,l0-tetrahydro-4H- 7 imidazo[2,1-c][1]benzothieno[2,3-e][1,4]diazepine as colorless fine needles, melting at 167169C.

EXAMPLE 4 10 g of -o-chlorophenyl7-ethyl-2-hydrazino-3H- thieno-[2,3-e][1,4]diazepine is suspended in 54 ml of 2 N hydrochloric acid. A solution of 2.4 g of sodium nitrite in 20 ml of water is added to the suspension at 5C with stirring. The mixture is stirred at room temperature for 30 minutes, and then alkalified with sodium carbonate. The precipitated crystals are filtered off and dissolved in chloroform, and the solution is washed with water. The chloroform layer is dried over anhydrous magnesium sulfate, and the chloroform is distilled off under reduced pressure. The reddish brown jelly-like residue thus obtained is crystallized from a mixture of ligroin and ethanol to give 8.2 g of 6-0- chlorophenyl-8-ethyl-4H-tetrazolo[5,1-c]thieno[2,3- e][1,4]diazepine as white crystals. The product, when recrystallized from ethanol, melts at l35136C.

EXAMPLE 5 g of. 5-o-chlorophenyl-2-hydrazino-7-methyl-3H- thieno[2,3-e][1,4]diazepine is suspended in 54 ml of 2 N hydrochloric acid. A solution of 2.26 g of sodium nitrite in 20 ml of water is added to the suspension at +5C with stirring. The mixture is stirred at room temperature for 1 hour, and alkalified with sodium carbonate. The precipitated crystals thus obtained are treated in the same manner as in Example 4 to give 7.9 g of 6- o-chlorophenyl-8-methyl-4H-tetrazolo- 5 ,1- c]thieno[2,3-e][1,4]diazepine as white crystals. This product, when recrystallized from ethanol, melts at 122 123C.

EXAMPLE 6 A solution of 10 g of 5-o-chlorophenyl-7-ethyl-2- hydroxyimino-l ,2-dihydro-3 I-l-thieno[2,3- e][1,4]diazepine and 7 g of triethylamine in 50 ml of toluene is added dropwise to 150 ml of 20% phosgene solution in toluene at 20.C with stirring. The mixture is stirred at room temperature for 4 hours, and then at 5060C with introduction of nitrogen gas to remove the excess phosgene. After cooling the reaction mixture, the precipitated triethylamine hydrochloride is removed by suction filtration, and the filtrate is concentrated under reduced pressure. The pale red jellylike residue obtained is crystallized from a mixture of ligoin and ethanol to give 7.5 g of 6-o-chlorophenyl-8- ethyl-1H,4H-[1,2,4]oxadiazolo[3 ,4-c]-thieno[2,3- e][1,4]diazepin-1-one as pale yellow crystals. This product, when recrystallized from ethanol, melts at l32133C.

EXAMPLE 7 A solution of 12.7 g of 5-o-chlorophenyl-2-hydroxyimino-7-methyl-1,2-dihydro-3H-thieno[2,3- e][1,4]diazepine and 10 g of triethylamine in 50 ml of tolueneis added dropwise to 150 ml of phosgene solution intoluene at 20C with stirring. The mixture is stirred at room temperature for 3.5 hours, and the reaction mixture is treated in the same manner as in Example 6 to give 9.6 g of 6-o-chlorophenyl-8-methyl- 1H,4H-[1,2,4]oxadiazolo[3,4-c]thieno[2,3- e][1,4]diazepin-1-one as pale yellow crystals. This product, when recrystallized from a mixture of ethanol and chloroform, melts at 154156C.

Using the procedure set forth in the above examples, but substituting equivalent amounts of the appropriate starting compounds, the following compounds are also produced:

(1) 6-phenyl-4H-imidazo[2, l -c]thieno[2,3-

e][1,4]diazepine, melting at 156157C;

(2) 6-o-chlorophenyl-8-methyl-4Himidazo[2, l c]thieno-[2,3-e][1,4]diazepine hydrochloride, melting at 25 225 3C with decomposition;

(3) 6-o-chlorophenyl-8-ethyl-4H-imidazo[2,1-

c]thieno[2,3-e]-[1,4]diazepine, melting at 180-182C;

(4) 6-o-bromophenyl-8-ethyl-4H-imidazo[2,1-

c ]thieno[2,3-e]-[ 1,4 ]diazepine hydrochloride, melting at 23723 8C;

(5) 8-ethyl-6-o -fluorophenyl-4H-imidazo[2, l c]thieno[2,3-e]-[1,4]diazepine mono hydrate, melting at -96C;

(6) 8-ethyl-6-p-fluorophenyl-4H-imidazo[2, 1 c]thieno[2,3-e]-[1,4]diazepine, melting at 1 16-1 17C;

(7) 8-ethyl-6-m-trifluoromethylphenyl-4H- imidazo[2,l-c]-thieno[2,3-e][1,4]diazepine;

(9) 8-ethyl-6-o-methoxyphenyl-4H-imidazo[2,1-

c]thieno-[2,3-e][1,4]diazepine dihydrochloride, melting at 2l5216C with decomposition;

( 10) 8-ethyl-6-p-methoxyphenyl-4H-imidazo[2,1-

c]thieno-[2,3-e][1,4]diazepine, melting at 173-175C;

(1 l 6-o-chlorophenyl-7,8-dimethyl-4H- imidazo[2,1-c]thieno-[2,3-e][1,4]diazepine, melting at 13l-132C;

( 12) 6-o-chlorophenyl-7,8,9,10-tetrahydro-4H- imidazo[2,l-c]-[l ]benzothieno[2,3-e][1,4]diazepine dihydrochloride, melting at 249251C with decomposition;

(13) 6-o-chlorophenyl-7,8-dimethyl-4H-tetrazolo[5,1-c]thieno-[2,3-e][1,4]diazepine, melting at 149150C;

(l4) 8-ethyl-6-phenyl-4H-tetrazolo[5 ,1-

c]thieno[2,3-e][1,4]-diazepine;

( l 5 8-ethyl-6-o-tolyl-4H-tetrazolo[ 5 ,1-

c]thieno[2,3-e][1,4]-diazepine;

( 16) 8-ethyl-6-o-methoxyphenyl-4H-tetrazolo[5 ,1-

c]thieno-[2,3-e][1,4]diazepine;

( 17) 8-ethyl-6-o-trifluoromethylphenyl-4H-tetrazolo[5,1-c]-thieno[2,3-e][1,4]diazepine;

( 18) 6-phenyl-7,8,9, l 0-tetrahydro-4H-tetrazolo[5 l c] 1 ]-benzothieno[2,3-e][ 1,4]diazepine, melting at l7ll72C;

(l9) 8-ethyl-6-phenyll H,4H-[ l,2,4]oxadiazolo[3,4- c]thieno-[2,3-e][1,4]diazepin-l-one hydrochloride, melting at 191-192C with decomposition;

(20) 6-o-chlorophenyl-7,8-dimethyl-1HAH- [l,2,4]oxadiazolo-[3,4-c]thieno[2,3-e][1,4]diazepin-l-one, melting at 136138C;

(21) 8-ethyl-6-o-tolyl-1H,4H-[ l,2,4]oxadiazolo[3,4-

c]thieno-[2,3-e][1,4]diazepin-1-one;

(22) 8-ethyl--o-methoxyphenyl-lH,4H-[1,2,41oxadiazolo[3,4-c]-thieno[2,3-e][1,4]diazepin-l-one;

(23) 8-ethyl-6-m-trif1uoromethylphenyl-l H,41-l- [1,2,4]oxadiazolo-[3,4-c]thieno[2,3-e][1,4]diazepin-l-one;

(24) 6-phenyl-7,8,9,10-tetrahydro-1H,4H-[ 1,2,4]oxadiazolo-[3,4-c][1 ]benzothieno[2,3-e][1,4]diazepin-l-one, melting at l49-l50C.

While the invention has been described in detail and in terms of specific embodiments thereof, it will be ap- 10 c]thieno[2,3-e l ,4 ]-diazepine. 2. The compound: 6-o-bromophenyl-8-ethyl-4H-imidazo[2,1-

c]thieno[2,3-e][ l,4]-diazepine. 3. The compound: 8-ethyl-6-o-fluorophenyl-4H-imidazo[ 2, 1

c]thieno[2,3-e][ l ,4]-diazepine. 

1. THE COMPOUND: 6-O-CHLOROPHENYL-8-ETHYL-4H-IMIDAZO(2,1-C)THIENOL(2,3E)(1,4)-DIAZEPINE.
 2. THE COMPOUND: 6-O-BROMOPHENYL-8-ETHYL-4H-IMIDAZO(2,1-C)THIENO(2,3E)(1,4)-DIAZEPINE.
 3. THE COMPOUND: 8-ETHYL-6-O-FLUOROPHENYL-4H-IMIDAZO(2,1-C)THIENO(2,3E)(1,4)-DIAZEPINE. 